A colorectal cancer classification system that associates cellular phenotype and responses to therapy

Anguraj Sadanandam, Costas A. Lyssiotis, Krisztian Homicsko, Eric A. Collisson, William J. Gibb, Stephan Wullschleger, Liliane C.Gonzalez Ostos, William A. Lannon, Carsten Grotzinger, Maguy Del Rio, Benoit Lhermitte, Adam B. Olshen, Bertram Wiedenmann, Lewis C. Cantley, Joe W. Gray, Douglas Hanahan

Research output: Contribution to journalArticle

512 Scopus citations

Abstract

Colorectal cancer (CRC) is a major cause of cancer mortality. Whereas some patients respond well to therapy, others do not, and thus more precise, individualized treatment strategies are needed. To that end, we analyzed gene expression profiles from 1,290 CRC tumors using consensus-based unsupervised clustering. The resultant clusters were then associated with therapeutic response data to the epidermal growth factor receptor-targeted drug cetuximab in 80 patients. The results of these studies define six clinically relevant CRC subtypes. Each subtype shares similarities to distinct cell types within the normal colon crypt and shows differing degrees of 'stemness' and Wnt signaling. Subtype-specific gene signatures are proposed to identify these subtypes. Three subtypes have markedly better disease-free survival (DFS) after surgical resection, suggesting these patients might be spared from the adverse effects of chemotherapy when they have localized disease. One of these three subtypes, identified by filamin A expression, does not respond to cetuximab but may respond to cMET receptor tyrosine kinase inhibitors in the metastatic setting. Two other subtypes, with poor and intermediate DFS, associate with improved response to the chemotherapy regimen FOLFIRI in adjuvant or metastatic settings. Development of clinically deployable assays for these subtypes and of subtype-specific therapies may contribute to more effective management of this challenging disease.

Original languageEnglish (US)
Pages (from-to)619-625
Number of pages7
JournalNature medicine
Volume19
Issue number5
DOIs
StatePublished - May 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'A colorectal cancer classification system that associates cellular phenotype and responses to therapy'. Together they form a unique fingerprint.

  • Cite this

    Sadanandam, A., Lyssiotis, C. A., Homicsko, K., Collisson, E. A., Gibb, W. J., Wullschleger, S., Ostos, L. C. G., Lannon, W. A., Grotzinger, C., Del Rio, M., Lhermitte, B., Olshen, A. B., Wiedenmann, B., Cantley, L. C., Gray, J. W., & Hanahan, D. (2013). A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nature medicine, 19(5), 619-625. https://doi.org/10.1038/nm.3175